Thionoesters and related thionolactones, R1CSOR2, are versatile intermediates for organic synthesis (Jones, B. A. and Bradshaw, J. S. 1984 Chem Rev. 84:17–30). For example, they may be transformed into ethers, R1CH2OR2, by reduction with Raney nickel (Baxter, S. L. and Bradshaw, J. S. 1981 J. Org. Chem. 46:831–832; Bradshaw et al. 1983 J. Org. Chem. 48:1127–1129) or tin hydrides (Smith et al. 1988 Phosphorus Sulfur 37:257–260; Jang et al. 1999 Tetrahedron 55:3479–3488) and into difluoroethers, R1CF2OR2, by treatment with (diethylamino)sulfur trifluoride (Bunnelle et al. 1990 J. Org. Chem. 55:768–770). Reaction of thionolactones with organometallic agents, R3M, leads to tetrahedral intermediates with may be trapped with methyl iodide and then reduced stereoselectively to alkylated cyclic ethers, R1R3CHOR2, a sequence which has proven valuable in the preparation of complex polyether natural products (Nicolaou et al. 1990 J. Am. Chem. Soc. 112:6263–6276; Nicolaou et al. 1995 J. Am. Chem. Soc. 1995 117:10227–10238). Of the possible precursors to thionoesters, the corresponding esters are highly attractive starting materials, being readily available commercially or by a variety of synthetic methods. However, the ester carbonyl group is one of the most difficult of the common carbonyl derivatives to thionate.
For example, the apparently straight-forward synthesis of thionoesters from esters using P4S10 suffers from generally low yields (Jones, B. A. and Bradshaw, J. S. 1984 Chem. Rev. 84:17–30). Replacing P4S10 with 2,4-(bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide (Lawesson's reagent, LR) results in improved yields of thionoesters and thionolactones, making these derivatives much more accessible and attractive as synthetic intermediates (Pederson et al. 1978 Bull. Soc. Chim. Belg. 87:293–297; Scheibye et al. 1979 Tetrahedron 35:1339–1343). However, the high equivalent weight of LR and the need to use a full mole of the reagent per mol of ester (Pederson et al. 1978 Bull. Soc. Chim. Belg. 87:293–297) means that the thionoester often comprises a small percent by weight of the crude reaction mixture. Because the reagent-derived byproducts cannot be removed by any extractive procedure, the total reaction mixture must be subjected to chromatography, and the method becomes impractical and expensive for large scale preparations. Moreover, chromatographic separation of the desired product from LR byproducts may, in some cases, be difficult or impossible.
Accordingly, there is a need for higher yield methods for production of thionoesters and thionolactones as these compounds are useful in a variety of technologies.
For example, the dithiolethiones (3H-1,2-dithiole-3-thiones) are a class of chemopreventive agents which display marked activity against a variety of animal models of cancer (Kensler, T. W. et al. 1994. ACS Sympos. Ser. 546:154–163). The basic structure of this class of compounds is shown below as Formula I. In fact, one representative of this class of heterocyclic sulfur compounds, known as oltipraz (R1=pyrazinyl, R2=methyl), is currently undergoing human trials in an area of China where there is a high incidence of liver cancer (Wang, J. et al. 1999. J. Natl. Cancer Inst. 91:347–354). In order to exploit the therapeutic potential of this compound and others that are chemically similar, methods of synthesis are needed that are both efficient (i.e., high yield) and cost-effective (i.e., require minimal post-reaction purification).
Unfortunately, the existing methods for synthesis of this sulfur-containing ring system are not optimum (Pedersen, C. T. 1982. Adv. Heterocycl. Chem. 31:63–113), especially for production and preparation of the large quantities of material that are needed for biological testing in animals, including humans. Current methods for synthesis of dithiolethiones employ reaction of a 3-oxoester with a mixture of P4S10 and sulfur. The reaction is generally conducted in boiling toluene or xylene (Schmidt, U. et al. 1960. Justus Liebigs Ann. Chem. 631:129–139; Lozach, N. and L. Legrand. 1952. C. R. Seances Acad. Sci. 234:1291–1293). However, the yields with this method are seldom above 50% and are typically low, in the range of 0 to 20% (Schmidt, U. et al. 1960. Justus Liebigs Ann. Chem. 631:129–139).
Replacing the P4S10 with LR, while resulting in higher yield of dithiolethiones, is still not practical for large scale preparations due to high cost and difficulty in separating the dithiolethiones from other byproducts.
Other attempts to improve the procedures for synthesis of the dithiolethione ring include treatment of 3-oxo dithioic acids with either a solution of polysulfanes in liquid hydrogen sulfide containing hydrogen bromide (Curphey, T. J. and H. H. Joyner. 1993. Tetrahedron Lett. 34:3703–3706) or with a combination of hexamethyldisilathiane and N-chlorosuccinimide in the presence of imidazole (Curphey, T. J. and H. H. Joyner. 1993. Tetrahedron Lett. 34:7231–7234). These synthetic procedures have also resulted in only limited success.